Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. Recently, we demonstrated that the Shh signaling is post-natally recapitulated upon ischemic injury of the adult skeletal muscle. We also found that the inhibition of the Shh pathway during skeletal muscle ischemia results in decreased angiogenic response. We also demonstrated that exogenous administration of Shh induces therapeutic angiogenesis in the ischemic muscle of old mice and that Shh intramyocardial gene transfer preserves heart function in myocardial ischemia, by enhancing neovascularization, reducing fibrosis, and increasing mobilization of bone marrow-derived endothelial progenitor cells. More recently, we have generated preliminary data showing that the Shh signaling pathway is also upregulated after mechanical and toxic injury of the skeletal muscle. In this setting, different cell types, including fibroblasts, macrophages, and satellite cells, respond to Shh activity. The aims of this proposal are: 1) to investigate the functional role of Shh on the activation of both angiogenesis- dependent and independent mechanisms that are important for muscle regeneration;2) to evaluate whether treatment with Shh improves regeneration in mouse models of skeletal muscle degeneration and dystrophy. The embryonic Shh signaling will be reconstituted by gene transfer of naked DNA encoding human Shh in the skeletal muscle of mice affected by ischemia, age- related muscle degeneration, or muscle dystrophy. We hypothesize that the activation of the Shh pathway will result in broad beneficial effects to muscle regeneration and repair, consistent with the role of this morphogen in embryogenesis, such as stimulation of angiogenesis and vasculogenesis, activation of muscle regulatory factors, and enhancement of the activity of muscle satellite cells. PUBLIC HEALTH RELEVANCE: We will use mouse models that are representative of important muscle diseases in humans. In particular, we will induce reconstitution of the embryonic Shh signaling in old mice (that have impaired muscular regenerative capacity, as observed in elderly individuals) and in mdx mice (a model of Duchenne muscular dystrophy). The results of this study might demonstrate that treatment with Shh may have considerable therapeutic potential in individuals with skeletal muscle diseases, by triggering expression of multiple trophic factors and engendering tissue repair in the adult.